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MECHANISM OF PHTHALATE INDUCED TESTICULAR TOXICITY

Award Number: R01ES011803
ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/30/2003
PERIOD OF PERFORMANCE END DATE: 06/30/2008

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MECHANISM OF PHTHALATE INDUCED TESTICULAR TOXICITY - DESCRIPTION (provided by applicant): The overall objective of this proposal is to determine the mechanisms by which phthalate esters downregulate testosterone production in the developing fetal rat testes, resulting in antiandrogenic effects on the developing male reproductive tract. Phthalate esters are a class of environmental chemicals to which humans are ubiquitously exposed and which cause antiandrogenic effects on the developing male reproductive tract in rats. The mechanisms by which phthalate esters cause their effects remain to be determined. In preliminary studies, global changes in gene expression in the developing rat testis following in utero exposure to di(n-butyl) phthalate (DBP) were examined. A significant finding was that DBP produced a reduction in key genes in pathways associated with either steroid production or the provision of substrates for this activity. It is therefore hypothesized that phthalates decrease testosterone in the developing testes because of a coordinate disruption in cholesterol transport and steroid biosynthesis. This hypothesis will be tested by investigating the following specific aims: 1) Identify the key steps involved in cholesterol transport and testosterone biosynthesis that are targets for disruption by in utero exposure to DBP in the developing fetal rat testes, 2) Determine the consequences of DBP-induced changes in target gene and protein expression identified in Specific Aim 1 on fetal testicular cell signaling pathways, cholesterol transport, and steroidogenesis, and 3) Establish the molecular mechanism by which DBP downregulates expression of genes involved in cholesterol transport and steroid biosynthesis. Quantitative RT-PCR and protein analysis will be used to identify gene targets in the developing fetal testis following in utero exposure to DBP. The promoter regions of selected gene target will be further examined in vitro to determine the mechanism by which phthalate esters act on cholesterol transport and steroidogenesis. The proposed studies will identify critical genes and pathways associated with cholesterol transport that are targets for DBP in the male rat in utero and will aid in determining potential human risks from exposure to this class of environmental chemicals.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2007 ( Subtotal = $271,605 )
2007	2007	CHEMICAL INDUSTRY INSTITUTE OF TOXICOLOGY	POST OFFICE BOX 12137	RESCH TRIANGLE PK	NC	27709		USA	Environmental Health	000	5	6/18/2007	NON-COMPETING CONTINUATION	$271,605
														Subtotal = $271,605

Issue Date FY: 2006 ( Subtotal = $279,717 )
2006	2006	CHEMICAL INDUSTRY INSTITUTE OF TOXICOLOGY	POST OFFICE BOX 12137	RESCH TRIANGLE PK	NC	27709		USA	Environmental Health	000	4	6/15/2006	NON-COMPETING CONTINUATION	$279,717
														Subtotal = $279,717

Issue Date FY: 2005 ( Subtotal = $286,449 )
2005	2005	CHEMICAL INDUSTRY INSTITUTE OF TOXICOLOGY	POST OFFICE BOX 12137	RESCH TRIANGLE PK	NC	27709		USA	Environmental Health	000	3	6/29/2005	NON-COMPETING CONTINUATION	$286,449
														Subtotal = $286,449

Issue Date FY: 2004 ( Subtotal = $286,449 )
2004	2004	CHEMICAL INDUSTRY INSTITUTE OF TOXICOLOGY	POST OFFICE BOX 12137	RESCH TRIANGLE PK	NC	27709		USA	Environmental Health	000	2	6/23/2004	NON-COMPETING CONTINUATION	$286,449
														Subtotal = $286,449

Issue Date FY: 2003 ( Subtotal = $286,449 )
2003	2003	CHEMICAL INDUSTRY INSTITUTE OF TOXICOLOGY	POST OFFICE BOX 12137	RESCH TRIANGLE PK	NC	27709		USA	Environmental Health	000	1	9/29/2003	NEW	$286,449
														Subtotal = $286,449

Grand Total All Awards = $1,410,669

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MECHANISM OF PHTHALATE INDUCED TESTICULAR TOXICITY

Award Number: R01ES011803

ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/30/2003

PERIOD OF PERFORMANCE END DATE: 06/30/2008

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